Methylmercury (MeHg) is a potent neurotoxin affecting both the developing and mature central nervous system (CNS) with apparent indiscriminate disruption of multiple homeostatic pathways. However, genetic and environmental modifiers contribute significant variability to neurotoxicity associated with human exposures. The long-term goal of this research is to elucidate the basis of MeHg neurotoxicity and to identify mechanistic- based neuroprotective strategies to mitigate human MeHg exposure risk. Here, we propose a multifaceted approach, combining powerful neurogenetic model systems, human-based cellular and genetic approaches to provide novel disease modifying strategies impinging on MeHg exposure vulnerability, and enable mechanistic insight into genetic pathways that modify sensitivity of specific neural lineages to MeHg-induced neurotoxicity. Specifically, we will test the hypothesis that genetic pathways that alter susceptibility to MeHg-induced neurotoxicity will display neural lineage- and developmental stage-dependent activity. In Specific Aim 1, we will screen for genetic modifiers of developmental MeHg-induced dopaminergic (DAergic) and glutamatergic (GLUergic) neurotoxicity in the nematode, C. elegans, by RNAi. Studies in Specific Aim 2 will compare and contrast MeHg neurotoxicological outcomes in human nigral DAergic versus cortical GLUergic neural lineages. Finally, in Specific Aim 3, we will evaluate mechanisms by which genetic pathways modify MeHg neurotoxicity. This highly interactive experimental design brings to bear innovative and complementary expertise to assess shared genetic networks attenuating MeHg-induced toxicity with translational extrapolation from the nematode to humans.